Systems Epigenomics of Persistent Bloodstream Infection

持续性血流感染的系统表观基因组学

• 批准号: 10551703
• 负责人: Michael R Yeaman
• 金额: $ 230.46万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551703
• 关键词: Acceleration; Address; Algorithms; Anti-Infective Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antifungal Agents; Antigens; Automobile Driving; Bacteremia; Bioinformatics; Blood; Blood Circulation; Candida; Candida albicans; Centers for Disease Control and Prevention (U.S.); Chromosomal Rearrangement; Clinical; Communicable Diseases; Computer Models; Computing Methodologies; DNA Methylation; Data; Data Set; Detection; Diagnostic; Disease; Disseminated candidiasis; Emergency Situation; Epigenetic Process; Etiology; Experimental Models; Fungemia; Gene Expression; Gene Rearrangement; Genetic; Genotype; Goals; Healthcare; Hematogenous; Hospital Mortality; Human; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunologic Memory; Immunotherapeutic agent; In Vitro; Infection; Intensive Care Units; Intervention; Laboratories; Laboratory Study; Length of Stay; Libraries; Life; Macrophage; Mediating; Memory; Methods; Microbial Biofilms; Modeling; Molecular; Morbidity - disease rate; Nosocomial Infections; Organ; Outcome; Pathogenesis; Patients; Pattern; Pattern recognition receptor; Phenotype; Predisposition; Process; Productivity; Receptor Signaling; Refractory; Research; Research Project Grants; Resistance; Risk; STAT protein; STAT1 protein; Sepsis; Specificity; Staphylococcus aureus; Stress; Study models; System; Systems Biology; Technology; Testing; Therapeutic; Tissues; Training; Translating; United States National Institutes of Health; Variant; Virulence; Work; antimicrobial; antimicrobial drug; antimicrobial tolerance; biobank; candidemia; cell injury; chronic infection; complex data; cytokine; data management; effective therapy; epigenetic memory; epigenome; epigenomics; high risk; improved; in vivo; innate immune mechanisms; innovation; insight; methicillin resistant Staphylococcus aureus; methylomics; mortality; mouse model; neutrophil; novel; novel strategies; pathogen; pharmacologic; prediction algorithm; predictive modeling; prevent; programs; prospective; prototype; response; screening; sex; success; synergism; therapeutic candidate; vaccine strategy

PROJECT ABSTRACT Persistent bloodstream infections are life-threatening infectious disease emergencies posing significant challenges to effective treatment. Such infections occur when a pathogen is susceptible to an anti-infective agent in vitro but is not cleared from the bloodstream in vivo when that anti-infective agent is used appropriately. As a result, anti-infective usage increases, accelerating alarming increases in anti-infective resistance. This vicious cycle of persistence driving anti- infective escalation driving resistance is an NIH high–priority concern. Bloodstream infections caused by Staphylococcus aureus (SA) or Candida albicans (CA) are increasingly common. Of urgent concern, up to 35% of patients with methicillin-resistant SA (MRSA) persistent bacteremia succumb even on gold-standard therapy. Likewise, in patients with hematogenously disseminated candidiasis (HDC), mortality is 39% overall and 47% in those in the intensive care unit, despite appropriate treatment. A disease mystery is central to such infections: the causative pathogen is susceptible to antimicrobials in laboratory testing—but not in the human being. Importantly, persistence reflects a unique type of treatment-refractory infections distinct from classical antibiotic resistance. Rather, persistent MRSA or CA are elusive: they adapt to host immune responses and antibiotic stresses uniquely in vivo and then revert quickly in vitro. Presently, there are few therapeutic options for persistent MRSA or CA bloodstream infections. Hence, there is a critical, unmet need to understand the unique interactions of the human, pathogen and therapeutic factors driving persistence outcomes. Based on our extensive preliminary data, we believe that persistent infections caused by MRSA and CA result from a three-way interaction of the pathogen, host immune response and antimicrobial agent in vivo. We hypothesize that persistent isolates: 1) have specific epigenomes to enable persistence; 2) subvert innate immune programming and memory for immune evasion; 3) evoke non-protective or maladaptive immune responses; and 4) exploit contextual immunity as persistence reservoirs. We further posit that conventional approaches to study this clinically urgent phenomenon are insufficient to understand it. We have developed three independent but synergistic research Projects to overcome these limitations. Each Project brings proven strengths and innovative approaches to bear on Specific Aims that synergize via a systems-based approach supported by outstanding technology, bioinformatics and computational Cores. Here, we will use state-of-the-art technologies to comprehensively analyze the genetics and epigenetics of pathogens and the host immune system in context of antimicrobial therapy in laboratory studies and experimental models of infection. In turn, these data will be analyzed using powerful bioinformatics and computational methods to detect hidden patterns within large complex datasets. By understanding these factors and their interactions, new approaches to identify and treat high risk patients can be developed and applied to improve and save lives. These goals are ideally aligned with priorities of the National Institutes of Health and Centers for Disease Control & Prevention.

项目摘要 持续性血流感染是威胁生命的传染病紧急情况， 有效的治疗。当病原体在体外对抗感染剂敏感但在体外对抗感染剂不敏感时， 当适当使用抗感染剂时，它会从体内的血液中清除。因此，抗感染药物的使用 增加，加速了抗感染抵抗力的惊人增长。这种持续驱动反- 感染升级驱动耐药性是NIH高度优先关注的问题。引起血流感染 金黄色葡萄球菌（SA）或白色念珠菌（CA）越来越常见。令人迫切关切的是， 耐甲氧西林金黄色葡萄球菌（MRSA）持续性菌血症的患者甚至在金标准疗法下也会死亡。同样地， 在血源性播散性念珠菌病（HDC）患者中，总体死亡率为39%， 重症监护室，尽管适当的治疗。一个疾病之谜是这种感染的核心： 病原体在实验室测试中对抗菌剂敏感，但在人类中却不敏感。重要的是，坚持 反映了一种独特类型的治疗难治性感染，不同于经典的抗生素耐药性。而是坚持不懈 MRSA或CA是难以捉摸的：它们在体内适应宿主免疫反应和抗生素应激，然后恢复 在试管内快速目前，持续性MRSA或CA血流感染的治疗选择很少。因此，我们认为， 有一个关键的，未满足的需要，了解独特的相互作用的人，病原体和治疗因素 推动持久性成果。 根据我们广泛的初步数据，我们认为MRSA和CA引起的持续感染是由以下原因引起的： 病原体、宿主免疫应答和抗菌剂在体内的三方相互作用。我们假设 持久性分离株：1）具有特定的表观基因组以实现持久性; 2）破坏先天免疫编程 3）诱发非保护性或适应不良的免疫反应;以及4）利用 背景免疫作为持久性储存库。我们进一步证实，传统的方法来研究这一临床 我们已经开发了三个独立但协同的研究， 克服这些限制的项目。每个项目都带来了经过验证的优势和创新的方法， 通过基于系统的方法协同作用的具体目标，由杰出的技术、生物信息学和 计算核心在这里，我们将使用最先进的技术来全面分析遗传学， 实验室研究中抗菌治疗背景下病原体和宿主免疫系统的表观遗传学， 感染的实验模型。反过来，这些数据将使用强大的生物信息学和计算分析， 在大型复杂数据集中检测隐藏模式的方法。通过了解这些因素及其相互作用， 可以开发和应用识别和治疗高风险患者的新方法来改善和挽救生命。这些 这些目标与美国国立卫生研究院和疾病控制与预防中心的优先事项理想地一致。